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Example of an EEG theta wave.

A theta rhythm is an oscillatory pattern in EEG signals
recorded either from inside the brain or from electrodes glued to
the scalp. Two types of theta rhythm have been described. The
"hippocampal theta rhythm" is a strong oscillation that
can be observed in the hippocampus and other brain structures in
numerous species of mammals
including rodents, rabbits, dogs, cats, bats, and marsupials.
"Cortical theta rhythms" are low-frequency components of
scalp EEG, usually recorded from humans.

In rats, the most frequently studied species, theta rhythmicity
is easily observed in the hippocampus, but can also be detected in
numerous other cortical and subcortical brain structures.
Hippocampal theta, with a frequency range of 6–10 Hz, appears when
a rat is engaged in active motor behavior such as walking or
exploratory sniffing, and also during REM sleep. Theta waves with a
lower frequency range, usually around 6–7 Hz, are sometimes
observed when a rat is motionless but alert. When a rat is eating,
grooming, or sleeping, the hippocampal EEG usually shows a
non-rhythmic pattern known as Large Irregular Activity or
LIA. The hippocampal theta rhythm depends critically on
projections from the medial septal area, which in turn
receives input from the hypothalamus and several brainstem areas.
Hippocampal theta rhythms in other species differ in some respects
from those in rats. In cats and rabbits, the frequency range is
lower (around 4–6 Hz), and theta is less strongly associated with
movement than in rats. In bats, theta appears in short bursts
associated with echolocation. In humans and other primates,
hippocampal theta is difficult to observe at all.

The function of the hippocampal theta rhythm is not clearly
understood. Green and Arduini, in the first major study of this
phenomenon, noted that hippocampal theta usually occurs together
with desynchronized EEG in the neocortex, and proposed that it is related to
arousal. Vanderwolf and his colleagues, noting the strong
relationship between theta and motor behavior, have argued that it
is related to sensorimotor processing. Another school, led by John
O'Keefe, have suggested that theta is part of the mechanism animals
use to keep track of their location within the environment. The
most popular theories, however, link the theta rhythm to mechanisms
of learning and memory.

Cortical theta rhythms observed in human scalp EEG are a
different phenomenon, with no clear relationship to the
hippocampus. In human EEG studies, the term theta refers
to frequency components in the 4–7 Hz range, regardless of their
source. Cortical theta is observed frequently in young children. In
older children and adults, it tends to appear during drowsy,
meditative, or sleeping states, but not during the deepest stages
of sleep. Several types of brain pathology can give rise to
abnormally strong or persistent cortical theta waves.

Terminology

Because of a historical accident, the term "theta rhythm" is
used to refer to two different phenomena, "hippocampal
theta" and "human cortical theta". Both of these are
oscillatory EEG patterns, but they may have little in common beyond
the name "theta".

Here is how the confusion arose: In the oldest EEG literature dating back to
the 1920s, Greek letters such as alpha, beta, theta, and gamma were
used to classify EEG waves falling into specific frequency ranges,
with "theta" generally meaning a range of about 4–7 cycles per
second (Hz). In the 1930s–1950s, a very strong rhythmic oscillation
pattern was discovered in the hippocampus of cats and rabbits (Green & Arduini, 1954). In these
species, the hippocampal oscillations fell mostly into the 4–6 Hz
frequency range, so they were referred to as "theta" oscillations.
Later, hippocampal oscillations of the same type were observed in
rats; however, the frequency of rat hippocampal EEG oscillations
averaged about 8 Hz and rarely fell below 6 Hz. Thus the rat
hippocampal EEG oscillation should not, strictly speaking, have
been called a "theta rhythm". However the term "theta" had already
become so strongly associated with hippocampal oscillations that it
continued to be used even for rats. Over the years this association
has come to be stronger than the original association with a
specific frequency range, but the original meaning also
persists.

The upshot is that "theta" can mean either of two things:

A specific type of regular oscillation seen in the hippocampus
and several other brain regions connected to it.

EEG oscillations in the 4–7 Hz frequency range, regardless of
where in the brain they occur or what their functional significance
is.

The first meaning is usually intended in literature that deals
with rats or mice, while the second meaning is usually intended in
studies of human EEG recorded using electrodes glued to the scalp.
In general, it is not safe to assume that observations of "theta"
in the human EEG have any relationship to the "hippocampal theta
rhythm". Scalp EEG is generated almost entirely by the cerebral
cortex, and even if it falls into a certain frequency range,
this cannot be taken to indicate that it has any functional
dependence on the hippocampus.

Hippocampal

Because of its densely packed neural layers, the hippocampus
generates some of the largest EEG signals of any brain structure.
In some situations the EEG is dominated by regular waves at 4–10
Hz, often continuing for many seconds. This EEG pattern is known as
the hippocampal theta rhythm. It has also been called
Rhythmic Slow Activity (RSA), to contrast it with the
Large Irregular Activity (LIA) that usually dominates the
hippocampal EEG when theta is not present.

In rats, hippocampal theta is seen mainly in two conditions:
first, when an animal is running, walking, or in some other way
actively interacting with its surroundings; second, during REM sleep
(Vanderwolf, 1969). The frequency
of the theta waves increases as a function of running speed,
starting at about 6.5 Hz on the low end, and increasing to about 9
Hz at the fastest running speeds, although higher frequencies are
sometimes seen for brief high-velocity movements such as jumps
across wide gaps. In larger species of animals, theta frequencies
are generally lower. The behavioral dependency also seems to vary
by species: in cats and rabbits, theta is often observed during
states of motionless alertness. This has been reported for rats as
well, but only when they are fearful (Sainsbury et al., 1987).

Theta is not just confined to the hippocampus. In rats, it can
be observed in many parts of the brain, including nearly all that
interact strongly with the hippocampus. The generation of the
rhythm is depends on the medial septal area: this area projects to
all of the regions that show theta rhythmicity, and destruction of
it eliminates theta throughout the brain (Stewart & Fox, 1990).

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Type 1 and
type 2

In 1975 Kramis, Bland, and Vanderwolf proposed that in rats
there are two distinct types of hippocampal theta rhythm, with
different behavioral and pharmacological properties (Kramis et al., 1975). Type 1 ("atropine
resistant") theta, according to them, appears during locomotion and
other types of "voluntary" behavior and during REM sleep, has a
frequency usually around 8 Hz, and is unaffected by the
anticholinergic drug atropine. Type 2 ("atropine sensitive") theta
appears during immobility and during anesthesia induced by urethane, has a frequency in
the 6–7 Hz range, and is eliminated by administration of atropine.
Many later investigations have supported the general concept that
hippocampal theta can be divided into two types, although there has
been dispute about the precise properties of each type. Type 2
theta is comparatively rare in unanesthetized rats: it may be seen
briefly when an animal is preparing to make a movement but hasn't
yet executed it, but has only been reported for extended periods in
animals that are in a state of frozen immobility because of the
nearby presence of a predator such as a cat or ferret (Sainsbury et al., 1987).

Relationship with
behavior

Vanderwolf (1969) made a strong
argument that the presence of theta in the hippocampal EEG can be
predicted on the basis of what an animal is doing, rather than why
the animal is doing it. Active movements such as running, jumping,
bar-pressing, or exploratory sniffing are reliably associated with
theta; inactive states such as eating or grooming are associated
with LIA. Later studies showed that theta frequently begins several
hundred milliseconds before the onset of movement, and that it is
associated with the intention to move rather than with feedback
produced by movement (Whishaw &
Vanderwolf, 1973). The faster an animal runs, the higher the
theta frequency. In rats, the slowest movements give rise to
frequencies around 6.5 Hz, the fastest to frequencies around 9 Hz,
although faster oscillations can be observed briefly during very
vigorous movements such as large jumps.

There is also a distinction between sleep states: REM (dreaming)
sleep is associated with theta; slow-wave sleep is associated with
LIA.

Mechanisms

Numerous studies have shown that the medial septal area plays a
central role in generating hippocampal theta (Stewart & Fox, 1990). Lesioning the
medial septal area, or inactivating it with drugs, eliminates both
type 1 and type 2 theta. Under certain conditions, theta-like
oscillations can be induced in hippocampal or entorhinal cells in
the absence of septal input, but this does not occur in intact,
undrugged adult rats. The critical septal region includes the
medial septal nucleus and the vertical limb of the diagonal band of
Broca. The lateral septal nucleus, a major recipient of hippocampal
output, probably does not play an essential role in generating
theta.

The medial septal area projects to a large number of brain
regions that show theta modulation, including all parts of the
hippocampus as well as the entorhinal cortex, perirhinal cortex,
retrosplenial cortex, medial mamillary and supramamillary nuclei of
the hypothalamus, anterior nuclei of the thalamus, amygdala,
inferior colliculus, and several brainstem nuclei (Buzsáki, 2002). Some of the projections
from the medial septal area are cholinergic; the rest are
GABAergic. It is commonly argued that cholergic receptors do not
respond rapidly enough to be involved in generating theta waves,
and therefore that GABAergic signals must play the central
role.

A major research problem has been to discover the "pacemaker"
for the theta rhythm, that is, the mechanism that determines the
oscillation frequency. The answer is not yet entirely clear, but
there is some evidence that type 1 and type 2 theta depend on
different pacemakers. For type 2 theta, the supramamillary nucleus
of the hypothalamus appears to exert control (Kirk, 1998). For type 1 theta, the picture
is still unclear, but the most widely accepted hypothesis proposes
that the frequency is determined by a feedback loop involving the
medial septal area and hippocampus (Wang,
2002).

Several types of hippocampal and entorhinal neurons are capable
of generating theta-frequency membrane potential oscillations when
stimulated. Typically these are sodium-dependent voltage-sensitive
oscillations in membrane potential at near-action
potential voltages (Alonso &
Llinás, 1989). Specifically, it appears that in neurons of the CA1 and dentate
gyrus, these oscillations result from an interplay of dendritic excitation via a
persistent sodium current (INaP) with
perisomatic inhibition (Buzsáki,
2002).

Generators

As a rule, EEG signals are generated by synchronized synaptic
input to the dendrites of neurons arranged in a layer. The
hippocampus contains multiple layers of very densely packed
neurons—the dentate gyrus and the CA3/CA1/subicular layer—and
therefore has the potential to generate strong EEG signals. Basic
EEG theory says that when a layer of neurons generates an EEG
signal, the signal always phase-reverses at some level. Thus, theta
waves recorded from site above and below a generating layer have
opposite signs. There are other complications as well: the
hippocampal layers are strongly curved, and theta-modulated inputs
impinge on them from multiple pathways, with varying phase
relationships. The outcome of all these factors is that the phase
and amplitude of theta change in a very complex way as a function
of position within the hippocampus. The largest theta waves,
however, are generally recorded from the vicinity of the fissure
that separates the CA1 molecular layer from the dentate gyrus
molecular layer. In rats, these signals frequently exceed 1
millivolt in amplitude. Theta waves recorded from above the
hippocampus are smaller, and polarity-reversed with respect to the
fissure signals.

The strongest theta waves are generated by the CA1 layer, and
the most significant input driving them comes from the entorhinal
cortex, via the direct EC→CA1 pathway. Another important driving
force comes from the CA3→CA1 projection, which is out of phase with
the entorhinal input, leading to a gradual phase shift as a
function of depth within CA1. The dentate gyrus also generates
theta waves, which are difficult to separate from the CA1 waves
because they are considerably smaller in amplitude, but there is
some evidence that dentate gyrus theta is usually about 90 degrees
out of phase from CA1 theta. Direct projections from the septal
area to hippocampal interneurons also play a role in generating
theta waves, but their influence is much smaller than that of the
entorhinal inputs (which are, however, themselves controlled by the
septum).

Humans
and other primates

In animals, EEG signals are usually recorded using electrodes
implanted in the brain; the majority of theta studies have involved
electrodes implanted in the hippocampus. In humans, because
invasive studies are not ethically permissible except in some
neurological patients, by far the largest number of EEG studies
have been conducted using electrodes glued to the scalp. The
signals picked up by scalp electrodes are comparatively small and
diffuse, and arise almost entirely from the cerebral cortex—the
hippocampus is too small and too deeply buried to generate
recognizable scalp EEG signals. Human EEG recordings show clear
theta rhythmicity in some situations, but because of the technical
difficulties, it has been difficult to tell whether these signals
have any relationship with the hippocampal theta signals recorded
from other species.

In contrast to the situation in rats, where long periods of
theta oscillations are easily observed using electrodes implanted
at many sites, theta has been difficult to pin down in primates,
even when intracortical electrodes have been available. Green and
Arduini (1954), in their pioneering
study of theta rhythms, reported only brief bursts of irregular
theta in monkeys. Other investigators have reported similar
results, although Stewart and Fox (1991) described a clear 7–9 Hz theta
rhythm in the hippocampus of urethane-anesthetized macaques and
squirrel monkeys, resembling the type 2 theta observed in
urethane-anesthetized rats.

Most of the available information on human hippocampal theta
comes from a few small studies of epileptic patients with
intracranially implanted electrodes used as part of a treatment
plan. In the largest and most systematic of these studies, Cantero
et al. (2003) found that
oscillations in the 4–7 Hz frequency range could be recorded from
both the hippocampus and neocortex. The hippocampal oscillations
were associated with REM sleep and the transition from sleep to
waking, and came in brief bursts, usually less than a second long.
Cortical theta oscillations were observed during the transition
from sleep and during quiet wakefulness; however, the authors were
unable to find any correlation between hippocampal and cortical
theta waves, and concluded that the two processes are probably
controlled by independent mechanisms.

Research findings in
theta-wave activity

Theta-frequency EEG activity is also manifested during some
short term memory tasks (Vertes, 2005).
Studies suggest that they reflect the "on-line" state of the
hippocampus; one of readiness to process incoming signals (Buzsáki, 2002). Conversely, theta
oscillations have been correlated to various voluntary behaviors
(exploration, spatial navigation, etc.) and alert states (piloerection, etc.) in rats (Vanderwolf, 1969), suggesting that it
may reflect the integration of sensory information with motor
output (for review, see Bland & Oddie,
2001). A large body of evidence indicates that theta rhythm is
likely involved in spatial learning and navigation (Buzsáki, 2005).

Theta rhythms are very strong in rodenthippocampi and entorhinal cortex during
learning and memory retrieval, and are believed to be vital to the
induction of long-term potentiation, a
potential cellular mechanism of learning and memory. Based on
evidence from electrophysiological studies showing that both
synaptic plasticity and strength of inputs to hippocampal region
CA1 vary systematically with ongoing theta oscillations (Hyman et al., 2003; Brankack et al., 1993), it has been
suggested that the theta rhythm functions to separate periods of
encoding of current sensory stimuli and retrieval of episodic
memory cued by current stimuli so as to avoid interference that
would occur if encoding and retrieval were simultaneous.

History

Although there were a few earlier hints, the first clear
description of regular slow oscillations in the hippocampal EEG
came from a paper written in German by Jung and Kornmüller (1938) They were not able to follow up on
these initial observations, and it was not until 1954 that further
information became available, in a very thorough study by John D.
Green and Arnaldo Arduini that mapped out the basic properties of
hippocampal oscillations in cats, rabbits, and monkeys (Green & Arduini, 1954). Their findings
provoked widespread interest, in part because they related
hippocampal activity to arousal, which was at that time the hottest
topic in neuroscience. Green and Arduini described an inverse
relationship between hippocampal and cortical activity patterns,
with hippocampal rhythmicity occurring alongside desynchronized
activity in the cortex, whereas an irregular hippocampal activity
pattern was correlated with the appearance of large slow waves in
the cortical EEG.

Over the following decade came an outpouring of experiments
examining the pharmacology and physiology of theta. By 1965,
Charles Stumpf was able to write a lengthy review of "Drug action
on the electrical activity of the hippocampus" citing hundreds of
publications (Stumpf, 1965), and in
1964 John Green, who served as the leader of the field during this
period, was able to write an extensive and detailed review of
hippocampal electrophysiology (Green,
1964). A major contribution came from a group of investigators
working in Vienna, including Stumpf and Wolfgang Petsche, who
established the critical role of the medial septum in controlling
hippocampal electrical activity, and worked out some of the
pathways by which it exerts its influence.

References

Bland,
BH; Oddie SD (2001). "Theta band oscillation and synchrony in the
hippocampal formation and associated structures: the case for its
role in sensorimotor integration". Behav Brain Res127: 119–36. doi:10.1016/S0166-4328(01)00358-8.